This program project has previously supported multidisciplinary research on the clinical pharmacology of a number of drugs that are used frequently in medical practice. A fundamental outgrowth of this research has been the development of a mathematical framework for characterizing the distribution of some compounds in terms of blood flow and transcapillary exchange components. Three of the four projects in this application deal with some aspect of this approach. In Project 1, we propose the first clinical studies using inulin and urea to calculate transcapillary exchange parameters. We will also conduct additional studies in animals to establish the physiological basis for some 3-compartment mammillary systems that are used to model drug distribution. In Project 2, we will determine whether theophylline distribution is flow limited in humans, as we have shown in dogs, and will further analyze changes in the distribution and elimination of this drug that occur in pregnant women, using inulin and urea as marker compounds. In a separate sub-project, we will explore in dogs the possibility that cocaine is another drug that exhibits flow-limited distribution kinetics. In Project 3, we will evaluate the possibility, suggested in our previous animal studies, that dialysisassociated skeletal muscle cramps are mediated in some patients by activation of the renin-angiotensin system. We will also use our kinetic method to characterize dialysis-associated changes in compartmental blood flow and will attempt to relate these changes to the presence or absence of skeletal muscle cramps. In Project 4, we will apply a novel stable isotope method that we developed to study N-acetylprocainamide bioavailability in elderly patients and in patients with renal failure and congestive heart failure. The research will have a clinical pharmacokinetic orientation and participating investigators have expertise in pharmacokinetics, drug metabolism and analytical methods, obstetrics and gynecology, nephrology, gastroenterology and cardiac surgery. All projects contain components that utilize stable isotope methods and are dependent on the mass spectrometry facility that is a major core resource for the program.